CN111533684A - Method for alkenylating pyridine compound - Google Patents
Method for alkenylating pyridine compound Download PDFInfo
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- CN111533684A CN111533684A CN202010477956.6A CN202010477956A CN111533684A CN 111533684 A CN111533684 A CN 111533684A CN 202010477956 A CN202010477956 A CN 202010477956A CN 111533684 A CN111533684 A CN 111533684A
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
- C07D213/16—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing only one pyridine ring
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
- C07D213/127—Preparation from compounds containing pyridine rings
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
The invention discloses a method for alkenylation of a pyridine compound, belonging to the technical field of organic synthesis. The method comprises the following steps: the compound of formula I is obtained by heating and reacting a mixture of quaternary pyridinium salt, internal alkyne, catalyst, ligand, monovalent copper salt, alkali and solvent. Formula I:
in the formula I, R includes R1And optionally R2Wherein R is1At the 2-position of the pyridine ring, R1Including alkyl or substituted phenyl; r2At any of positions 3 to 5 of the pyridine ring, R2Including alkyl, substituted alkyl or phenyl, and Ar includes alkyl, phenyl or substituted phenyl. The method uses a quaternary ammonium activation strategy to carry out the olefination reaction of the pyridine substrate, overcomes the defects of harsh conditions, complicated reaction steps and the like of the traditional method for synthesizing the substances, and has the advantages of wide substrate range, good reaction selectivity and higher yield.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a method for alkenylating a pyridine compound.
Background
The pyridine compounds are important heterocycles, are ubiquitous framework materials, and can exist in the fields of medicines, natural products, functional materials, agricultural chemistry and the like. Thus, efforts have been made to functionalize pyridine to obtain more pyridine derivatives.
Although there are many methods for introducing alkenyl groups, such as nucleophilic substitution, Friedel-crafts alkylation and Tsuji-Trostanylation, these methods generally suffer from a limited substrate range, the formation of a large amount of by-products, harsh reaction conditions, and pre-functionalization. In addition, the low activity of pyridine compounds for aromatic electrophilic substitution is a great challenge.
Currently, there is a great room for improvement in the synthesis of alkenylated pyridine compounds.
In view of this, the invention is particularly proposed.
Disclosure of Invention
The invention aims to provide a method for alkenylating a pyridine compound, which can effectively overcome the defects of harsh conditions, complicated reaction steps and the like of substances for synthesizing the pyridine compound in the past, and has the advantages of wide substrate range and good reaction selectivity.
The invention is realized by the following steps:
the invention provides a method for alkenylating a pyridine compound, which comprises the following steps:
carrying out heating reaction on a mixture of pyridine quaternary ammonium salt, internal alkyne, a catalyst, a ligand, a monovalent copper salt, alkali and a solvent to obtain a compound shown in a formula I:
the structural formula of formula I is:
in the formula I, R includes R1And optionally R2Wherein R is1At the 2-position of the pyridine ring, R1Including alkyl or substituted phenyl; r2At any of positions 3 to 5 of the pyridine ring, R2Including alkyl, substituted alkyl or phenyl, and Ar includes alkyl, phenyl or substituted phenyl.
Preferably, the compound of formula I comprises
Any one of the above;
in an alternative embodiment, the compound of formula I comprises the Z form product and the E form product in a total yield of 56 to 97%, preferably 90 to 97%.
In an alternative embodiment, the ratio of product form Z to product form E in the compound of formula i is (3.4-9): 1, preferably (8.6-9): 1.
In an alternative embodiment, the heating reaction is carried out at 100-150 ℃ for 15-32h, preferably at 120 ℃ for 20 h.
In an alternative embodiment, the quaternized pyridinium salt comprises N-methyl quaternized pyridinium salt.
In an alternative embodiment, the quaternized pyridinium salt is prepared from primarily pyridine and methyl iodide.
In alternative embodiments, the quaternary ammonium salt of pyridine includes 2-pentylpyridinium quaternary ammonium salt, 2- (pentan-3-yl) pyridinium quaternary ammonium salt, 2- (3-methylbutan-2-yl) pyridinium quaternary ammonium salt, 2- (3-methylglutaryl) pyridinium quaternary ammonium salt, 2- (4-methylhexan-3-yl) pyridinium quaternary ammonium salt, 2- (4-methylglutaryl) pyridinium quaternary ammonium salt, 2-cyclohexylpyridinium quaternary ammonium salt, 2-phenylpyridinium quaternary ammonium salt, 2- (p-toluene) pyridinium quaternary ammonium salt, 2- (4-methoxyphenyl) pyridinium quaternary ammonium salt, 2- (4-fluorophenyl) pyridinium quaternary ammonium salt, 2- (4-chlorophenyl) pyridinium quaternary ammonium salt, 3-methyl-2- (p-toluene) pyridinium quaternary ammonium salt, m, 2- (4-chlorophenyl) -3-methylpyridine quaternary ammonium salt, 2- (4-nitrophenyl) -3-methylpyridine quaternary ammonium salt, 2, 4-diphenylpyridine quaternary ammonium salt, 4- (tert-butyl) -2-phenylpyridine quaternary ammonium salt, 3-methyl-2-phenylpyridine quaternary ammonium salt, 2- (thiophen-2-yl) pyridine quaternary ammonium salt or 2-cyclohexylpyridine quaternary ammonium salt.
In an alternative embodiment, the internal alkyne comprises a benzene-containing internal alkyne.
In alternative embodiments, the internal alkyne comprises 1-phenyl-1-propyne, tolane, or 1, 2-bis (3, 5-dimethylphenyl) acetylene.
In an alternative embodiment, the internal alkyne is produced primarily from diynoic acid and bromobenzene.
In an alternative embodiment, the catalyst comprises a transition metal catalyst.
In an alternative embodiment, the transition metal catalyst comprises a palladium catalyst.
In alternative embodiments, the palladium catalyst comprises Pd (OAc)2、Pd(PhCN)2Cl2、[Pd(Cl)(C3H5)]2Or PdCl2Preferably Pd (OAc)2。
In an alternative embodiment, the ligand comprises a phosphine ligand.
In alternative embodiments, the phosphine ligand comprises a phosphine ligand comprising triphenylphosphine, tricyclohexylphosphine tetrafluoroborate, 1, 4-bis (diphenylphosphino) butane, 1, 2-bis (diphenylphosphino) ethane, or 2,2 '-diphenylphosphinomethyl-1, 1' -biphenyl, preferably tricyclohexylphosphine tetrafluoroborate.
In alternative embodiments, the monovalent copper salt comprises CuI, CuBr, CuCl, CuCN, or CuSCN; CuBr is preferred.
In an alternative embodiment, the base comprises an inorganic base.
In an alternative embodiment, the inorganic base comprises potassium pivalate.
In alternative embodiments, the base further comprises an organic base.
In an alternative embodiment, the organic base comprises triethylamine.
In an alternative embodiment, when the base comprises both inorganic base and organic base, the inorganic base is used in an amount of 0.05 to 0.3 equivalent and the organic base is used in an amount ratio of 10 to 50 mol% based on the amount of the quaternary ammonium salt of pyridine.
In an alternative embodiment, when the base includes both inorganic base and organic base, the inorganic base is used in an amount of 0.1 equivalent and the organic base is used in an amount of 30 mol% based on the amount of the quaternary ammonium salt of pyridine.
In an alternative embodiment, when the base comprises both an inorganic base and an organic base, the amount of the catalyst is 5 to 10 mol%, the amount of the cuprous salt is 30 to 80 mol%, the amount of the ligand is 10 to 50 mol%, the amount of the organic base is 10 to 50 mol%, and the amount of the inorganic base is 0.05 to 0.3 equivalent, based on the amount of the quaternary pyridinium salt; preferably, the catalyst is used in an amount of 10 mol%, the monovalent copper salt is used in an amount of 50 mol%, the ligand is used in an amount of 30 mol%, the organic base is used in an amount of 0.3 equivalent, and the inorganic base is used in an amount of 30 mol%.
In an alternative embodiment, the solvent comprises fluorobenzene, N-dimethylacetamide and water.
In an alternative embodiment, the concentration of fluorobenzene is 0.43 to 1.0mol/L, preferably 0.75 mol/L.
In an optional embodiment, the method further comprises a post-treatment step, wherein the post-treatment step mainly comprises washing, solvent removal and extraction of the reacted filtrate, and column chromatography separation of the extracted organic phase.
In an alternative embodiment, the washing reagent comprises at least one of dichloromethane and ethyl acetate.
In an alternative embodiment, the desolventization is performed by evaporation under reduced pressure.
In an alternative embodiment, the reagents used for extraction are the same as those used for washing.
In an alternative embodiment, the column used for column chromatography is a silica gel column.
In an alternative embodiment, the mobile phase used for column chromatography is petroleum ether and ethyl acetate.
The beneficial effects of the invention include:
the method for alkenylating the pyridine compound provided by the invention is used for heating and reacting a mixture of quaternary ammonium salt of pyridine, internal alkyne, a catalyst, a ligand, a cuprous salt, alkali and a solvent to obtain the alkenylated pyridine compound. The method is carried out by adopting a quaternary ammonium activation strategy, the reaction operation is simple, the raw materials are easy to obtain, the substrate range is wide, and the yield is high.
Wherein, 1) the pyridine is very easy to have quaternization reaction and can be carried out in situ in a C-H functionalized system, so that an activating group is not required to be installed in advance; 2) the quaternary pyridinium salt has a stronger C-H acidity than the pyridine nitroxide and, therefore, a higher activity for C-H functionalization; 3) the functionalized quaternary pyridinium salt can spontaneously undergo de-quaternization under the influence of increased steric hindrance with the aid of nucleophiles in the system, and therefore, no additional reaction step is required to remove the activated group. The method synthesizes alkenyl pyridine substances through the steps of C-H activation, olefin insertion, reduction elimination and the like under the catalysis of a catalyst, and overcomes the defects of harsh conditions, complicated reaction steps and the like of the traditional synthesis of the substances.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
The method for alkenylating the pyridine compound provided by the present application is specifically described below.
Since the pyridine N atom is easy to coordinate with metal, so that the catalyst is poisoned and loses activity, the most effective method at present is to protect the N terminal, such as oxidizing the pyridine N atom into pyridine oxynitride and then performing C-H activation functionalization, but the method needs to install an activation group in advance, and an additional reaction step is needed to remove the activation group after the de-quaternization reaction, so that the conditions are harsh and the operation is complicated.
The inventor has long studied and proposed a method for carrying out the olefination reaction of pyridine substrate by using the strategy of quaternary ammonium salt of pyridine. The "quaternized pyridinium strategy" described above refers to: pyridine and methyl iodide are refluxed in acetonitrile to obtain quaternary pyridinium salt, C-H functionalization is further carried out, and demethylation reaction is spontaneously carried out on the functionalized quaternary pyridinium salt under the influence of increased steric hindrance.
The method may for example comprise the steps of:
the compound of formula I is obtained by heating and reacting a mixture of quaternary pyridinium salt, internal alkyne, catalyst, ligand, monovalent copper salt, alkali and solvent.
The structural formula of formula I is:
in the formula I, R includes R1And optionally R2Wherein R is1At the 2-position of the pyridine ring, R1Including alkyl or substituted phenyl; r2At any of positions 3 to 5 of the pyridine ring, R2Including alkyl, substituted alkyl or phenyl, and Ar includes alkyl, phenyl or substituted phenyl.
In the application, the quaternary pyridinium salt is used as a reaction substrate, and has a substituent R on a pyridine ring of the quaternary pyridinium salt in a way of matching with the formula I, wherein R comprises R1And optionally R2(i.e., the quaternary pyridinium salt may have R on the pyridine ring2Or may not have R2)。
Above as R1The alkyl group of (b) is preferably an alkyl group having 1 to 7 carbon atoms, the substituent in the substituted phenyl group may be selected from, for example, an alkyl group, a halogen group, a cyano group or the like, and the number of the substituents may be 1 to 2.
R2For example, it may include alkyl, substituted alkyl or phenyl, as R2The alkyl group of (b) is preferably an alkyl group having 1 to 4 carbon atoms, such as a methyl group, a methoxy group, a tert-butyl group or the like.
In an alternative embodiment, compounds of formula IThe object may for example comprise
Any one of them.
In an alternative embodiment, the compounds of formula i include the Z-form and the E-form, both of which are cis-trans isomers.
In the present application, the yield of the Z-form product and the E-form product is 56-97% in total, and in some preferred embodiments, the yield of the Z-form product and the E-form product is 90-97% in total.
In alternative embodiments, the ratio of product form Z to product form E in the compound of formula i may be (3.4 to 9): 1. in some preferred embodiments, the ratio of Z form product to E form product is (8.6-9): 1.
In an alternative embodiment, the heating reaction is carried out at 100-150 ℃ for 15-32 h. Preferably, the heating reaction is carried out at 120 ℃ for 20 h. The conditions for the heating reaction are set to the above ranges in the present application for reasons including: the reaction effect is best under the condition.
In an alternative embodiment, the quaternary pyridinium salt is mainly N-methyl quaternary pyridinium salt, and the chemical structural formula of the quaternary pyridinium salt is as follows:
the N-methyl pyridine quaternary ammonium salt is mainly prepared from pyridine and methyl iodide, and the preparation method can be referred to documents adv.Synth.Catal.2018,360, 3990-3998. Furthermore, direct acquisition by purchase is not excluded.
As a referential example, the above-mentioned quaternary ammonium salt of pyridine may include, but is not limited to, 2-pentylquaternary ammonium salt of pyridine, 2- (pentan-3-yl) quaternary ammonium salt of pyridine, 2- (3-methylbutan-2-yl) quaternary ammonium salt of pyridine, 2- (3-methylglutaryl) quaternary ammonium salt of pyridine, 2- (4-methylhexan-3-yl) quaternary ammonium salt of pyridine, 2- (4-methylglutaryl) quaternary ammonium salt of pyridine, 2-cyclohexylquaternary ammonium salt of pyridine, 2-phenylpyridine quaternary ammonium salt, 2- (p-toluene) quaternary ammonium salt of pyridine, 2- (4-methoxyphenyl) quaternary ammonium salt of pyridine, 2- (4-fluorophenyl) quaternary ammonium salt of pyridine, 2- (4-chlorophenyl) quaternary ammonium salt of pyridine, 2- (3-methyl), 3-methyl-2- (p-toluene) quaternary ammonium pyridinium salt, 2- (4-chlorophenyl) -3-methylpyridinium quaternary ammonium salt, 2- (4-nitrophenyl) -3-methylpyridinium quaternary ammonium salt, 2, 4-diphenylpyridinium quaternary ammonium salt, 4- (tert-butyl) -2-phenylpyridinium quaternary ammonium salt, 3-methyl-2-phenylpyridinium quaternary ammonium salt, 2- (thiophen-2-yl) pyridinium quaternary ammonium salt or 2-cyclohexylpyridinium quaternary ammonium salt.
Correspondingly, the structural formula of the quaternary ammonium pyridine salt is as follows in sequence:
the compound is used as a substrate, so that the quaternization reaction of pyridine can be carried out in situ in a C-H functionalized system without installing an activating group in advance.
In this application, an internal alkyne is used as alkyne, i.e., a substituent other than H is attached to both ends of the hydrocarbon group. The use of a terminal hydrocarbon group does not allow the relevant olefination to occur.
In alternative embodiments, the internal alkyne can include 1-phenyl-1-propyne, tolane, or 1, 2-bis (3, 5-dimethylphenyl) acetylene.
By reference, the internal alkynes in the present application are mainly prepared from diynoic acid and bromobenzene, and the preparation method thereof can be referred to in j. org. chem.,2010,75, 6244-. Furthermore, direct acquisition by purchase is not excluded.
As described above, the quaternary pyridinium salt and the internal alkyne serve as a main reaction body for alkenylation of the pyridine compound, and the double bond of the alkyne is opened and the quaternary pyridinium salt is inserted into the opened double bond during the reaction.
In an alternative embodiment, the catalyst used in the reaction process comprises a transition metal catalyst. Preferably, the transition metal catalyst comprises a palladium catalystAgents, e.g. Pd (OAc)2、Pd(PhCN)2Cl2、[Pd(Cl)(C3H5)]2Or PdCl2Etc., preferably comprises (or is preferably) Pd (OAc)2In order to obtain higher yield of the product.
It is worth to be noted that, in the present application, the reaction rate can be effectively increased compared with other transition metal elements by using the transition metal palladium as a catalyst.
In an alternative embodiment, the ligands include phosphine ligands, which are specifically configured based on the palladium catalyst employed in the present application, and which are capable of facilitating the reaction of the present application more readily than other types of ligands. It is to be noted that the ligands used in the reactions of the present application do not exclude other non-phosphine ligands.
In alternative embodiments, the phosphine ligand includes, for example, triphenylphosphine, tricyclohexylphosphine tetrafluoroborate, 1, 4-bis (diphenylphosphino) butane, 1, 2-bis (diphenylphosphino) ethane, or 2,2 '-diphenylphosphinomethyl-1, 1' -biphenyl, etc., preferably includes (or is preferably) triphenylphosphine or tricyclohexylphosphine tetrafluoroborate (in this application (Cy)3P.HBF4Representation).
In an alternative embodiment, the monovalent copper salt is used primarily in the present application to interact with the quaternary ammonium salt, and in particular, may comprise CuI, CuBr, CuCl, CuCN or CuSCN, preferably comprising (or preferably being) CuBr.
In alternative embodiments, the base comprises an inorganic base, such as potassium pivalate (PivOK).
Further, the base may also include an organic base, such as triethylamine (Et)3N)。
In an alternative embodiment, when the base comprises both organic base and inorganic base, the amount of the organic base is 10 to 50 mol% and the amount of the inorganic base is 0.05 to 0.3 equivalent based on the amount of the quaternary ammonium salt; preferably, the organic base is used in an amount of 0.1 equivalent and the inorganic base is used in an amount of 30 mol%.
It is to be noted that the yield of the Z-form compound is about 60 to 90% when only the inorganic base is used, and substantially 90% when both the organic base and the inorganic base are used. In an alternative embodiment, the solvent may comprise, for example, fluorobenzene, N-dimethylacetamide and water. Wherein, fluorobenzene is mainly used for dissolving products, and N, N-dimethylacetamide is mainly used for promoting the dissolution of the quaternary ammonium salt as the raw material. The yield of the Z-type compound can reach 90% by taking the three substances as the solvent and combining the reaction process.
In an alternative embodiment, the concentration of fluorobenzene may be, for example, 0.43 to 1.0mol/L, preferably 0.75 mol/L.
In an alternative embodiment, the amount of the catalyst is 5 to 10 mol%, the amount of the cuprous salt is 30 to 80 mol%, the amount of the ligand is 10 to 50 mol%, the amount of the organic base is 10 to 50 mol%, and the amount of the inorganic base is 0.05 to 0.3 equivalent based on the amount of the quaternary pyridinium salt. Wherein the amount of quaternary ammonium salt of pyridine may be 0.3-5mmol, such as 0.3mmol, 0.5mmol, 1mmol, 1.5mmol, 2mmol, 2.5mmol, 3mmol, 3.5mmol, 4mmol, 4.5mmol or 5 mmol.
In an alternative embodiment, the amount of the catalyst is 10 mol%, the amount of the cuprous salt is 50 mol%, the amount of the ligand is 30 mol%, the amount of the organic base is 30 mol%, and the amount of the inorganic base is 0.1 equivalent based on the amount of the quaternary pyridinium salt.
Taking palladium catalyst as Pd (OAc)2The cuprous salt is CuBr, and the phosphine ligand is (Cy)3P.HBF4The inorganic base is PivOK, and the organic base is Et3For example, the general chemical reaction formula for alkenylation of pyridine compounds in the present application can be referred to as follows:
in an optional embodiment, the method further comprises a post-treatment step, wherein the post-treatment step mainly comprises washing, solvent removal and extraction of the reacted filtrate, and column chromatography separation of the extracted organic phase.
In an alternative embodiment, the washing reagent comprises at least one of dichloromethane and ethyl acetate, preferably dichloromethane.
In an alternative embodiment, the desolventization is performed by evaporation under reduced pressure.
In an alternative embodiment, the reagents used for the extraction are the same as those used for washing, and the organic phase is subjected to column chromatography after extraction.
In an alternative embodiment, the column used for column chromatography is a silica gel column.
In an alternative embodiment, the mobile phase used for column chromatography is petroleum ether and ethyl acetate, which may be present in a volume ratio of 50 to 200:1, preferably 100: 1.
In summary, the method for alkenylating a pyridine compound provided by the present application comprises heating a mixture of a quaternary ammonium salt of pyridine, an internal alkyne, a catalyst, a ligand, a monovalent copper salt, a base, and a solvent to react, thereby obtaining the alkenylated pyridine compound. The method adopts a quaternary ammonium activation strategy, has simple reaction operation, easily obtained raw materials, wider substrate range and higher yield, synthesizes alkenyl pyridine substances through the steps of C-H activation, olefin insertion, reduction elimination and the like under the catalysis of a catalyst, and overcomes the defects of harsh conditions, complicated reaction steps and the like of synthesizing the substances in the past.
The features and properties of the present invention are described in further detail below with reference to examples.
Melting points of the compounds of the following examples were measured by XRC-I type micro melting point apparatus (Sichuan Dake cheian apparatus length) with thermometer uncorrected; NMR spectra were obtained by 1H NMR of Bruker DPX-400MHz NMR spectrometer (solvent: CDCl)3Or DMSO-d6Internal standard TMS),13c NMR (solvent: CDCl)3Or DMSO-d6TMS internal standard); high resolution mass spectrometry was performed using a WaterMicromass GCT mass spectrometer (ESI source).
All metal reagents were analytical grade and were not treated before use.
The reagents used were: tricyclohexylphosphine tetrafluoroborate (beijing enokay technologies ltd) is analytically pure. Potassium pivalate was synthesized according to literature procedures, and all other bases were analytically pure. Alkyne reagents were synthesized according to literature methods, and all of the internal alkyne reagents (Beijing Yinokay science and technology Co., Ltd.) were analytically pure.
Main solvent: fluorobenzene and N, N-dimethylacetamide were both analytical pure.
Thin layer chromatography [ HFGF 254 silica gel plate ] (Qingdao maritime works); column chromatography silica gel (100-.
The substrate N-methylpyridine quaternary ammonium salts used in the examples were prepared from pyridine and iodomethane according to the methods of the corresponding references above, and the alkyne reagents were prepared from diynoic acid and bromobenzene according to the methods of the corresponding references above. Other reagents were purchased directly from reagents such as TCI, Aldrich and Adamas without further purification.
Example 1
The present example provides a method for preparing a compound represented by formula I-a.
The preparation method comprises the following steps: to a dry 20mL reaction tube under air was added the stir bar Pd (OAc)2(0.03mmol)、CuBr(0.15mmol)、(Cy)3P·HBF4(30 mol%), PivOK (0.3mmol), diphenylalkyne (0.6mmol) and 2-pentylpyridinium quaternary ammonium salt (0.3mmol), and then triethylamine (30 mol%), water (50uL), DMAc (0.1mL) and fluorobenzene (0.25mL) are added, and after the reagent is added, the mixture is heated and stirred in the reactor at 120 ℃ for 20 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered through a glass funnel lined with celite, washed with dichloromethane, the filtrates were combined and the solvent was evaporated under reduced pressure, selecting petroleum ether/ethyl acetate ═ 100: and 1 is a mobile phase, and the product is obtained by adopting flash silica gel column chromatography purification.
The product of this example was obtained in 90% yield (Z: E ═ 9: 1).
The compound of formula I-a is a light yellow oil, and its structure is characterized as follows:
1H NMR(400MHz,CDCl3)7.56(t,J＝7.7Hz,1H),7.40-7.27(m,5H),7.21(s,1H),7.15-7.10(m,3H),7.07(dd,J＝7.8,0.8Hz,1H),7.04-6.99(m,3H),2.51-2.41(m,1H),2.02-1.93(m,1H),1.82-1.91(m,1H),1.77-1.67(m,1H),1.00(d,J＝6.7Hz,3H),0.83-0.71(m,6H)。
13C NMR(101MHz,CDCl3)165.3,158.7,142.2,141.6,137.2,136.5,129.6,129.0,128.3,128.0,127.6,127.2,126.9,122.8,121.6,57.1,32.9,25.3,21.4,20.8,12.5。
HRMS(ESI)m/z:calc for[C25H28N]+:342.2216；Found:342.2210。
example 2
In this example, a method of preparing a compound represented by formula I-b is provided.
In this example, 2- (pentan-3-yl) pyridinium quaternary ammonium salt was used instead of 2-pentylpyridinium quaternary ammonium salt in example 1, and the preparation conditions and procedure were the same as in example 1.
The product of this example was obtained in 85% yield (Z: E ═ 7.4: 1).
The compound of formula I-b is a light yellow oil, and its structure is characterized as follows:
1H NMR(400MHz,CDCl3)7.64(t,J＝7.7Hz,1H),7.49-7.30(m,5H),7.23-7.11(m,5H),7.09-7.04(m,3H),2.79-2.65(m,1H),1.82-1.71(m,4H),0.88(t,J＝7.4Hz,6H)。
13C NMR(101MHz,CDCl3)165.7,158.8,142.1,141.6,137.2,136.7,129.5,129.3,128.3,128.0,127.6,127.2,127.0,122.9,120.9,51.6,28.4,12.2。
HRMS(ESI)m/z:calc for[C24H26N]+:328.2060；Found:328.2047。
example 3
The present example provides methods for preparing compounds of formula I-c.
In this example, 2- (3-methylbutan-2-yl) pyridinium quaternary ammonium salt was used instead of 2-pentylpyridinium quaternary ammonium salt in example 1, and the preparation conditions and procedure were the same as in example 1.
The product of this example was obtained in 86% yield (Z: E ═ 8.6: 1).
The compounds of formula I-c are light yellow oils, the structures of which are characterized as follows:
1H NMR(400MHz,CDCl3)7.64(t,J＝7.7Hz,1H),7.49-7.30(m,5H),7.23-7.11(m,5H),7.09-7.04(m,3H),2.79-2.65(m,1H),1.82-1.71(m,4H),0.88(t,J＝7.4Hz,6H)。
13C NMR(101MHz,CDCl3)167.0,158.6,142.2,141.7,137.2,136.7,129.6,129.4,128.3,128.0,127.6,127.3,127.0,122.8,120.3,48.9,33.5,21.6,19.8,17.5。
HRMS(ESI)m/z:calc for[C24H26N]+:328.2060；Found:328.2059。
example 4
The present example provides methods for preparing compounds of formula I-d.
In this example, 2- (3-methylglutaryl) quaternary ammonium pyridine salt was used instead of 2-pentylquaternary ammonium pyridine salt in example 1, and the preparation conditions and procedure were the same as in example 1.
The product of this example was obtained in 86% yield (Z: E ═ 7.7: 1).
The compounds of formula I-d are light yellow oils, the structures of which are characterized as follows:
1H NMR(400MHz,CDCl3)7.56(td,J＝7.7,1.7Hz,1H),7.42-7.27(m,5H),7.19(s,1H),7.17-7.07(m,5H),7.06-6.97(m,3H),2.90-2.77(m,1H),1.86-1.70(m,1H),1.58-1.47(m,1H),1.37-1.30(m,1H),1.32-1.23(m,3H),1.21-0.99(m,1H),0.93-0.76(m,6H)。
13C NMR(101MHz,CDCl3)167.0,158.6,142.2,141.7,137.2,136.6,129.4,129.3,128.3,128.0,127.6,127.3,126.9,122.7,120.3,46.9,39.7,27.9,25.8,15.4,11.7。
HRMS(ESI)m/z:calc for[C25H28N]+:342.2216；Found:342.2213。
example 5
The present example provides methods for preparing compounds of formula I-e.
In this example, 2- (4-methylhexan-3-yl) pyridinium quaternary ammonium salt was used instead of 2-pentylpyridinium quaternary ammonium salt in example 1, and the preparation conditions and procedure were the same as in example 1.
The product of this example was obtained in 75% yield (Z: E ═ 7.3: 1).
The compounds of formula I-e are light yellow oils, the structures of which are characterized as follows:
1H NMR(400MHz,CDCl3)7.55(t,J＝7.7Hz,1H),7.40-7.27(m,5H),7.20(s,1H),7.15-7.10(m,3H),7.07(d,J＝7.7Hz,1H),7.04-6.97(m,3H),2.62-2.53(m,1H),1.90-1.68(m,3H),1.59-1.52(m,1H),1.35-1.27(m,1H),1.22-1.13(m,1H),0.97-0.87(m,3H),0.84-0.73(m,6H)。
13C NMR(101MHz,CDCl3)165.4,158.7,142.2,141.6,137.2,136.5,129.6,129.0,128.3,127.9,127.6,127.2,126.9,122.7,121.7,55.1,39.1,27.2,24.9,16.7,12.5,11.3。
HRMS(ESI)m/z:calc for[C26H30N]+:356.2373；Found:356.2369。
example 6
The present example provides a method for preparing compounds of formula I-f.
In this example, 2- (4-methylglutaryl) quaternary ammonium pyridine salt was used instead of 2-pentylquaternary ammonium pyridine salt in example 1, and the preparation conditions and procedure were the same as in example 1.
The product of this example was obtained in 88% yield (Z: E ═ 7.0: 1).
The compounds of formula I-f are light yellow oils, the structures of which are characterized as follows:
1H NMR(400MHz,CDCl3)7.56(t,J＝7.7Hz,1H),7.41-7.36(m,2H),7.36-7.27(m,3H),7.17(d,J＝7.1Hz,1H),7.17-7.07(m,4H),7.03-6.95(m,3H),3.09-2.99(m,1H),1.76-1.62(m,1H),1.47-1.34(m,2H),1.25(d,J＝6.9Hz,3H),0.87(dd,J＝11.3,6.3Hz,6H)。
13C NMR(101MHz,CDCl3)167.4,158.7,142.3,141.8,137.3,136.9,129.6,129.5,128.4,128.0,127.7,127.4,127.0,122.9,119.8,46.4,40.0,26.0,23.3,22.6,21.8。
HRMS(ESI)m/z:calc for[C25H28N]+:342.2216；Found:342.2215。
example 7
The present example provides a method for preparing compounds of formula I-g.
In this example, 2-cyclohexylpyridinium quaternary ammonium salt was used in place of 2-pentylpyridinium quaternary ammonium salt in example 1, and the other preparation conditions and procedure were the same as in example 1.
The product of this example was obtained in 72% yield (Z: E ═ 7.2: 1).
The compounds of formulas I-g are yellow oils and are structurally characterized as follows:
1H NMR(400MHz,CDCl3)7.56(t,J＝7.7Hz,1H),7.40-7.36(m,2H),7.35-7.27(m,3H),7.17-7.09(m,5H),7.02-6.92(m,3H),2.81-2.70(m,1H),1.94(d,J＝12.0Hz,2H),1.85-1.79(m,2H),1.77-1.69(m,1H),1.55-1.35(m,4H),1.28-1.22(m,1H)。
13C NMR(101MHz,CDCl3)167.0,158.5,142.2,141.8,137.2,137.0,129.6(d,J＝8.0Hz),128.3,128.0,127.6,127.4,127.0,122.8,119.0,46.5,33.0,26.6,26.2。
HRMS(ESI)m/z:calc for[C25H26N]+:340.2060；Found:340.2060。
example 8
The present example provides methods for preparing compounds of formula I-h.
In this example, 2-phenylpyridine quaternary ammonium salt was used in place of 2-pentylpyridine quaternary ammonium salt in example 1, and the other preparation conditions and procedure were the same as in example 1.
The product of this example was obtained in 97% yield (Z: E ═ 7.1: 1).
The compounds of formulae I-h are yellow oils and are structurally characterized as follows:
1H NMR(400MHz,CDCl3)7.87(dd,J＝7.8,1.5Hz,2H),7.74-7.65(m,2H),7.48-7.35(m,3H),7.17-7.10(m,2H),7.06(s,2H),6.97(s,1H),6.81(s,1H),6.68(s,2H),2.33(s,6H),2.16(s,6H)。
13C NMR(101MHz,CDCl3)159.5,157.4,142.2,142.1,139.7,137.7,137.3(d,J＝4.4Hz),137.1,130.3,129.3,128.8,128.7,127.5,127.2,125.6,124.1,119.0,21.5,21.3。
HRMS(ESI)m/z:calc for[C29H28N]+:390.2216；Found:390.2216。
example 9
The present example provides a method for preparing a compound represented by formula I-I.
In this example, 2- (p-toluene) quaternary ammonium pyridinium salt was used instead of 2-pentylquaternary ammonium salt in example 1, and the preparation conditions and procedure were the same as in example 1.
The product of this example was obtained in 89% yield (Z: E ═ 6.4: 1).
The compounds of formulas I-g are yellow oils and are structurally characterized as follows:
1H NMR(400MHz,CDCl3)7.81(d,J＝8.2Hz,2H),7.72-7.65(m,2H),7.28-7.24(m,2H),7.15-7.09(m,4H),6.99(s,1H),6.82(s,1H),6.71(s,2H),2.43(s,3H),2.35(s,6H),2.18(s,6H)。
13C NMR(101MHz,CDCl3)159.4,157.4,142.2(d,J＝5.8Hz),138.8,137.7,137.3,137.0,130.2,129.4,129.3,128.6,127.5,127.1,125.6,123.8,118.6,21.5,21.3(d,J＝3.2Hz)。
HRMS(ESI)m/z:calc for[C30H30N]+:404.2373；Found:404.2373。
example 10
The present example provides a method for preparing a compound represented by formula I-j.
In this example, 2- (4-methoxyphenyl) quaternary ammonium pyridinium salt was used instead of 2-pentylquaternary ammonium salt in example 1, and the preparation conditions and procedure were the same as in example 1.
The product of this example was obtained in 81% yield (Z: E ═ 5.2: 1).
The compound of formula I-j is a yellow oil, and its structure is characterized as follows:
1H NMR(400MHz,CDCl3)7.87-7.81(m,2H),7.69-7.59(m,2H),7.12-7.06(m,4H),6.99-6.92(m,3H),6.81(s,1H),6.69(s,2H),3.86(s,3H),2.33(s,6H),2.16(s,6H)。
13C NMR(101MHz,CDCl3)160.4,159.3,157.0,142.2(d,J＝9.7Hz),137.7,137.3,137.0,132.4,130.1,129.3,128.6,128.5,127.5,125.6,123.4,118.2,114.0,55.4,21.5,21.3。
HRMS(ESI)m/z:calc for[C30H30NO]+:420.2322；Found:420.2321。
example 11
The present example provides a method for preparing a compound represented by formula I-k.
In this example, 2- (4-fluorophenyl) pyridium quaternary ammonium salt was used in place of 2-pentylpyridium quaternary ammonium salt in example 1, and the preparation conditions and procedure were the same as in example 1.
The product of this example was obtained in 77% yield (Z: E ═ 5.4: 1).
The compounds of formula I-k are yellow oils and are structurally characterized as follows:
1H NMR(400MHz,CDCl3)7.85-7.78(m,2H),7.73-7.64(m,1H),7.65-7.59(m,1H),7.16-7.04(m,6H),6.97(s,1H),6.81(s,1H),6.67(s,2H),2.33(s,6H),2.15(s,6H)。
13C NMR(101MHz,CDCl3)164.8,162.3,159.5,156.4,142.2,137.7,137.3(d,J＝15.9Hz),137.2,135.9,130.5,129.4,129.1(d,J＝8.3Hz),128.7,127.4,125.6,124.1,118.6,115.6,21.5,21.3。
HRMS(ESI)m/z:calc for[C29H27FN]+:408.2122；Found:408.2122。
example 12
The present example provides a method for preparing a compound represented by formula I-l.
In this example, 2- (4-chlorophenyl) pyridinium quaternary ammonium salt was used instead of 2-pentylpyridinium quaternary ammonium salt in example 1, and the preparation conditions and procedure were the same as in example 1.
The product of this example was obtained in 81% yield (Z: E ═ 5.2: 1).
The compounds of formula I-l are light yellow oils, the structures of which are characterized as follows:
1H NMR(400MHz,CDCl3)7.81-7.75(m,2H),7.75-7.75(m,1H),7.67-7.60(m,1H),7.42-7.36(m,2H),7.16(dd,J＝7.5,0.9Hz,1H),7.12(s,1H),7.06(s,2H),6.98(s,1H),6.82(s,1H),6.67(s,2H),2.34(s,6H),2.16(s,6H)。
13C NMR(101MHz,CDCl3)159.6,156.1,142.0,138.1,137.7,137.4,137.3,137.2,135.0,130.5,129.4,128.8,128.7,128.5,127.4,125.6,124.4,118.7,21.5,21.3。
HRMS(ESI)m/z:calc for[C29H26ClN]+:424.1827；Found:424.1820。
example 13
The present example provides a method for preparing a compound represented by formula I-m.
In this example, 3-methyl-2- (p-toluene) pyridiniumquaternary ammonium salt was used in place of 2-pentylpyridiniumquaternary ammonium salt in example 1, and the preparation conditions and procedure were the same as in example 1.
The product of this example was obtained in 82% yield (Z: E ═ 5.4: 1).
The compounds of formula I-m are yellow oils and are structurally characterized as follows:
1H NMR(400MHz,CDCl3)7.55(d,J＝7.9Hz,1H),7.33(d,J＝8.1Hz,2H),7.23(d,J＝7.9Hz,2H),7.10(d,J＝5.3Hz,4H),6.98(s,1H),6.85(s,1H),6.69(s,2H),2.46(s,3H),2.42(s,3H),2.36(s,6H),2.22(s,6H)。
13C NMR(101MHz,CDCl3)158.3,156.7,142.2,142.0,138.9,137.9,137.5(d,J＝6.0Hz),137.2,130.0,129.2,129.0,128.7,128.4,127.5,125.6,123.7,21.4,21.3,20.1。
HRMS(ESI)m/z:calc for[C31H32N]+:418.2529；Found:418.2529。
example 14
The present example provides a method for preparing compounds of formula I-n.
In this example, 2- (4-chlorophenyl) -3-methylpyridinium quaternary ammonium salt was used instead of 2-pentylpyridinium quaternary ammonium salt in example 1, and the preparation conditions and procedure were the same as in example 1.
The product of this example was obtained in 82% yield (Z: E ═ 5.8: 1).
The compounds of formula I-n are yellow oils and are structurally characterized as follows:
1H NMR(400MHz,CDCl3)7.55(d,J＝8.0Hz,1H),7.37-7.32(m,2H),7.30-7.26(m,2H),7.10(d,J＝7.8Hz,1H),7.04(d,J＝11.7Hz,3H),6.96(s,1H),6.83(s,1H),6.63(s,2H),2.42(s,3H),2.32(s,6H),2.18(s,6H)。
13C NMR(101MHz,CDCl3)157.0,142.1,141.8,139.2,139.1,137.7,137.5,137.3,133.9,130.7,130.4,129.4,129.1,128.5,128.3,127.5,125.7,124.3,21.5,21.3,20.0。
HRMS(ESI)m/z:calc for[C30H29ClN]+:438.1983；Found:438.1981。
example 15
The embodiment provides a method for preparing a compound shown in a formula I-o by an N-methylpyridine quaternary ammonium salt olefination reaction.
In this example, 2- (4-nitrophenyl) -3-methylpyridinium quaternary ammonium salt was used instead of 2-pentylpyridinium quaternary ammonium salt in example 1, and the preparation conditions and procedure were the same as in example 1.
The product of this example was obtained in 56% yield (Z: E ═ 5.2: 1).
The compounds of formula I-o are yellow oils and are structurally characterized as follows:
1H NMR(400MHz,CDCl3)8.24-8.18(m,2H),7.61-7.57(m,1H),7.48-7.43(m,2H),7.15(d,J＝7.9Hz,1H),7.05(s,1H),6.97(d,J＝12.0Hz,3H),6.83(s,1H),6.61(s,2H),2.42(s,3H),2.31(s,6H),2.17(s,6H)。
13C NMR(101MHz,CDCl3)157.4,155.7,147.4,147.0,142.0,141.6,139.5,137.8,137.5,137.4,130.8,130.4,129.5(d,J＝4.2Hz),128.6,127.5,125.7,125.2,123.4,21.5,21.4,19.9。
HRMS(ESI)m/z:calc for[C30H29N2O2]+:449.2224；Found:449.2221。
example 16
The present example provides a method for preparing a compound represented by formula I-p.
In this example, 2, 4-diphenylpyridinium quaternary ammonium salt was used instead of 2-pentylpyridinium quaternary ammonium salt in example 1, and the preparation conditions and procedure were the same as in example 1.
The product of this example was obtained in 79% yield (Z: E ═ 5.1: 1).
The compounds of formula I-p are colorless oils and are structurally characterized as follows:
1H NMR(400MHz,CDCl3)8.01-7.97(m,2H),7.96-7.92(m,1H),7.68-7.60(m,2H),7.53-7.44(m,7H),7.19(d,J＝10.0Hz,3H),7.03(s,1H),6.86(s,1H),6.80(s,2H),2.39(s,6H),2.21(s,6H)。
13C NMR(101MHz,CDCl3)160.0,158.1,149.6,142.2(d,J＝10.2Hz),139.8,138.7,137.7,137.3(d,J＝6.9Hz),130.6,129.4,129.1,129.0,128.9,127.5,127.3,127.2,125.7,122.4,117.2,21.5,21.3。
HRMS(ESI)m/z:calc for[C35H32N]+:466.2529；Found:466.2527。
example 17
The present example provides a method for preparing compounds of formula I-q.
In this example, 4- (tert-butyl) -2-phenylpyridine quaternary ammonium salt was used instead of 2-pentylpyridine quaternary ammonium salt in example 1, and the preparation conditions and procedure were the same as in example 1.
The product of this example was obtained in 86% yield (Z: E ═ 6.2: 1).
The compounds of formulae I-q are light yellow oils, the structures of which are characterized as follows:
1H NMR(400MHz,CDCl3)7.95-7.89(m,2H),7.68(d,J＝1.7Hz,1H),7.48-7.38(m,3H),7.18(d,J＝1.7Hz,1H),7.13(d,J＝2.5Hz,3H),6.98(s,1H),6.79(s,1H),6.64(s,2H),2.35(s,6H),2.16(s,6H),1.29(s,9H)。
13C NMR(101MHz,CDCl3)160.8,159.2,157.6,142.6,142.1,140.4,137.6,137.4,137.2,130.2,129.2,128.6(d,J＝6.0Hz),127.4(d,J＝9.1Hz),125.6,122.0,116.0,34.9,30.6,21.5,21.3。
HRMS(ESI)m/z:calc for[C36H36N]+:446.2842；Found:446.2840。
example 18
The present example provides a method for preparing compounds of formula I-r.
In this example, 3-methyl-2-phenylpyridine quaternary ammonium salt was used in place of 2-pentylpyridine quaternary ammonium salt in example 1, and the other preparation conditions and procedure were the same as in example 1.
The product of this example was obtained in 90% yield (Z: E ═ 5.4: 1).
The compounds of formula I-r are yellow oils and are structurally characterized as follows:
1H NMR(40MHz,CDCl3)7.53(d,J＝7.8Hz,1H),7.39-7.32(m,5H),7.06(d,J＝7.8Hz,1H),7.02(d,J＝6.4Hz,3H),6.93(s,1H),6.80(s,1H),6.62(s,2H),2.41(s,3H),2.30(s,6H),2.16(s,6H)。
13C NMR(101MHz,CDCl3)158.4,156.8,142.2,141.9,139.0,137.7,137.5,137.3,130.1,129.3,129.2,128.5,128.1,127.8,127.5,125.7,124.0,21.5,21.4,20.1。
HRMS(ESI)m/z:calc for[C30H30N]+:404.2373；Found:404.2371.
example 19
The present example provides a method for preparing compounds of formula I-s.
In this example, 2- (thien-2-yl) pyridinium quaternary ammonium salt was used instead of 2-pentylpyridinium quaternary ammonium salt in example 1, and the other preparation conditions and procedure were the same as in example 1.
The product of this example was obtained in 65% yield (Z: E ═ 4.0: 1).
The compounds of formula I-s are light yellow oils, the structures of which are characterized as follows:
1H NMR(400MHz,CDCl3)7.80-7.75(m,1H),7.68-7.60(m,1H),7.59-7.53(m,2H),7.38-7.32(m,1H),7.11-7.05(m,4H),6.97(s,1H),6.80(s,1H),6.69(s,2H),2.33(d,J＝0.7Hz,6H),2.16(d,J＝0.7Hz,6H)。
13C NMR(101MHz,CDCl3)159.5,153.5,142.5,142.2,142.0,137.7,137.3,137.2,137.0,130.3,129.3,128.7,127.5,126.6,126.0,125.6,123.9,118.7,21.5,21.3。
HRMS(ESI)m/z:calc for[C27H26NS]+:396.1780；Found:396.1781。
example 20
The present example provides a method for preparing compounds of formula I-t.
In this example, 2-cyclohexylpyridinium quaternary ammonium salt was used in place of 2-pentylpyridinium quaternary ammonium salt in example 1, and the other preparation conditions and procedure were the same as in example 1.
The product of this example was obtained in 57% yield (Z: E ═ 3.4: 1).
The compounds of formula I-t are pale yellow oils, the structures of which are characterized as follows:
1H NMR(400MHz,CDCl3)7.67-7.62(m,2H),7.55-7.50(m,1H),7.07(s,1H),7.05-7.00(m,3H),6.98(dd,J＝3.4,0.7Hz,1H),6.94(s,1H),6.77(s,1H),6.66(s,2H),6.50(dd,J＝3.4,1.8Hz,1H),2.30(s,6H),2.14(s,6H)。
13C NMR(101MHz,CDCl3)159.6,154.0,149.6,143.2,142.0,141.7,137.7,137.3,137.0,130.2,129.3,128.8,127.5,125.4,124.0,116.9,112.1,109.1,21.5,21.3。
HRMS(ESI)m/z:calc for[C27H26NO]+:380.2009；Found:380.2009。
in summary, the yield of the method for the N-methylpyridine quaternary ammonium salt olefination reaction provided by the application can reach 90% at most (Z: E is 9:1), the reaction condition is mild, the operation is simple, the raw materials are easy to obtain, the substrate can be converted into various other useful molecules, and the method has strong practicability.
The above is only a preferred embodiment of the present invention, and is not intended to limit the present invention, and various modifications and changes will occur to those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A process for alkenylating a pyridine compound, comprising the steps of:
carrying out heating reaction on a mixture of pyridine quaternary ammonium salt, internal alkyne, a catalyst, a ligand, a monovalent copper salt, alkali and a solvent to obtain a compound shown in a formula I:
the structural formula of formula I is:
in the formula I, R includes R1And optionally R2Wherein R is1At the 2-position of the pyridine ring, R1Including alkyl or substituted phenyl; r2At any of positions 3 to 5 of the pyridine ring, R2Including alkyl, substituted alkyl or phenyl, Ar includes alkyl, phenyl or substituted phenyl;
preferably, the compound of formula I comprises
And
any one of the above;
preferably, the compound of formula i comprises a product of form Z and a product of form E, the ratio of the product of form Z to the product of form E being (3.4 to 9):1, more preferably (8.6-9) 1;
preferably, the heating reaction is carried out at 100-150 ℃ for 15-32h, more preferably at 120 ℃ for 20 h.
2. The method of claim 1, wherein the quaternized pyridinium salt comprises N-methyl quaternized pyridinium salt;
preferably, the quaternary pyridinium salt is mainly prepared from pyridine and methyl iodide;
preferably, the quaternary ammonium salt of pyridine includes 2-pentylquaternary ammonium salt of pyridine, 2- (pentan-3-yl) quaternary ammonium salt of pyridine, 2- (3-methylbutan-2-yl) quaternary ammonium salt of pyridine, 2- (3-methylglutaryl) quaternary ammonium salt of pyridine, 2- (4-methylhexan-3-yl) quaternary ammonium salt of pyridine, 2- (4-methylglutaryl) quaternary ammonium salt of pyridine, 2-cyclohexylquaternary ammonium salt of pyridine, 2-phenylpyriquaternary ammonium salt of pyridine, 2- (p-toluene) quaternary ammonium salt of pyridine, 2- (4-methoxyphenyl) quaternary ammonium salt of pyridine, 2- (4-fluorophenyl) quaternary ammonium salt of pyridine, 2- (4-chlorophenyl) quaternary ammonium salt of pyridine, 3-methyl-2- (p-toluene) quaternary ammonium salt of pyridine, 2- (3-methyl-2, 2- (4-chlorophenyl) -3-methylpyridine quaternary ammonium salt, 2- (4-nitrophenyl) -3-methylpyridine quaternary ammonium salt, 2, 4-diphenylpyridine quaternary ammonium salt, 4- (tert-butyl) -2-phenylpyridine quaternary ammonium salt, 3-methyl-2-phenylpyridine quaternary ammonium salt, 2- (thiophen-2-yl) pyridine quaternary ammonium salt or 2-cyclohexylpyridine quaternary ammonium salt.
3. The method of claim 1, wherein the internal alkyne comprises a benzene-containing internal alkyne;
preferably, the internal alkyne comprises 1-phenyl-1-propyne, tolane, or 1, 2-bis (3, 5-dimethylphenyl) acetylene;
preferably, the internal alkyne is produced predominantly from diynoic acid and bromobenzene.
4. The method of claim 1, wherein the catalyst comprises a transition metal catalyst;
preferably, the transition metal catalyst comprises a palladium catalyst;
more preferably, the palladium catalyst comprises Pd (OAc)2、Pd(PhCN)2Cl2、[Pd(Cl)(C3H5)]2Or PdCl2Further more preferably, the palladium catalyst is Pd (OAc)2。
5. The method of claim 1, wherein the ligand comprises a phosphine ligand;
preferably, the phosphine ligand comprises triphenylphosphine, tricyclohexylphosphine tetrafluoroborate, 1, 4-bis (diphenylphosphino) butane, 1, 2-bis (diphenylphosphino) ethane or 2,2 '-diphenylphosphinomethyl-1, 1' -biphenyl;
more preferably, the phosphine ligand is tricyclohexylphosphine tetrafluoroborate.
6. The method of claim 1, wherein the monovalent copper salt comprises CuI, CuBr, CuCl, CuCN, or CuSCN; CuBr is preferred.
7. The method of claim 1, wherein the base comprises an inorganic base;
preferably, the inorganic base comprises potassium pivalate;
preferably, the base further comprises an organic base;
preferably, the organic base comprises triethylamine;
preferably, when the base comprises the inorganic base and the organic base at the same time, the amount of the inorganic base is 0.05 to 0.3 equivalent and the amount of the organic base is 10 to 50mol percent based on the amount of the quaternary ammonium salt;
more preferably, the inorganic base is used in an amount of 0.1 equivalent, and the organic base is used in an amount of 30 mol%.
8. The method according to claim 7, wherein when the base comprises both the inorganic base and the organic base, the amount of the catalyst is 5 to 10 mol%, the amount of the monovalent copper salt is 30 to 80 mol%, the amount of the ligand is 10 to 50 mol%, the amount of the organic base is 10 to 50 mol%, and the amount of the inorganic base is 0.05 to 0.3 equivalent based on the amount of the quaternary pyridinium salt;
preferably, based on the amount of the quaternary ammonium salt of pyridine, the amount of the catalyst is 10 mol%, the amount of the cuprous salt is 50 mol%, the amount of the ligand is 30 mol%, the amount of the organic base is 30 mol%, and the amount of the inorganic base is 0.1 equivalent.
9. The method of claim 1, wherein the solvent comprises fluorobenzene, N-dimethylacetamide and water.
10. The method as claimed in claim 1, further comprising a post-treatment step, wherein the post-treatment step mainly comprises washing, solvent removal and extraction of the reacted filtrate, and column chromatography separation of the extracted organic phase;
preferably, the washing reagent comprises at least one of dichloromethane and ethyl acetate;
preferably, the solvent removal is carried out by evaporation under reduced pressure;
preferably, the reagents used for extraction are the same as those used for washing;
preferably, the chromatographic column used for column chromatography is a silica gel column chromatographic column;
preferably, the mobile phase used for column chromatography is petroleum ether and ethyl acetate.
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